The mammalian nuclear factor kappa beta (NF-κB) system consists of five NF-κB subunits—RelA, c-Rel, RelB, p50, and p52—and five proteins with inhibitory activity—IκBa, IκBb, IκB3, p105, and p100. NF-κB subunits interact with each other forming homo- and heterodimers. The NF-κB1 and NF-κB2 proteins, p105 and p100, are the precursors of p50 and p52. The rate of processing of the p105 and p100 regulates the availability of NF-κB dimers (Savinova et al., 2009, Mol Cell 34, 591-602). The degradation of inhibitory proteins bound to the NF-κB subunits leads to translocation of the NF-κB homo- or heterodimers into the nucleus. Here, they initiate transcription of NF-κB-controlled genes, resulting in pro-inflammatory responses and signals for cell survival and proliferation (Nishikori 2005, J Clin Exp Hematol 45: 15-24). Activation of the NF-κB pathway with a nuclear translocation of NF-κB dimers containing p50 is typically referred to as the classical (or canonical, or p105) NF-κB activation pathway. Similarly, activation of the NF-κB pathway with a nuclear translocation of NF-κB dimers containing p52 is typically referred to as the alternative (or noncanonical, or p100) NF-κB activation pathway (Nishikori 2005, J Clin Exp Hematol 45: 15-24).
NF-κB pathway activation can be induced under physiological conditions by stimulation of cells with certain ligands, or due to intrinsic dysregulation of the molecular machinery controlling the NF-κB system. For example, mutations discovered in positive and negative regulators of NF-κB can constitutively activate the NF-κB pathway (Compagno et al., 2009, Nature 459, 717-721). Activation of NF-κB is detected in a number of human lymphomas, including adult T-cell lymphoma and B cell lymphomas, such as primary mediastinal B cell lymphomas, primary effusion lymphoma, mucosa-associated lymphoid tissue lymphoma, primary effusion lymphoma, a subtype of non-Hodgkins lymphoma, diffuse large B cell lymphoma (DLBCL), and activated B cell like (ABC) DLBCL (Davis et al., 2001, J Exp Med 12: 1861-74; Alizadeh et al., 2000, Nature 6769: 503-11; Rosenwald et al., 2003, Leuk Lymphoma pp S41-S47; Rosenwald et al., 2003, J Exp Med 6: 851-62; Ho et al., 2005; Blood 7: 2891-99; Keller et al., 2000, Blood 7: 2537-42; Wang et al, 2009, PLoS ONE 4(4):e5360. Epub 2009 Apr. 24). NF-κB activation leads to suppression of anti-apoptotic pathways and production of pro-inflammatory cytokines that further induce proliferation of lymphoid cells (Wang et al, 2009, PLoS ONE 4(4):e5360. Epub 2009 Apr. 24; Auphan et al, 1995, Science 5234, 286-90).
Treatments for these diverse types of lymphomas vary from surgery, chemotherapy, hormonal therapy, radiation treatment, and more recently, immunotherapy with agents such as rituximab (US2011/0223157; Stockdale 1998, Medicine, Vol 3, Rubenstein and Federman eds., Chapter 12, Section IV; US2009/0203050). See also. U.S. Pat. No. 7,166,639 and US2011/0223157. However, each of these therapies, or therapy combinations, has its own drawbacks for the patients, including toxicity and systemic immunosuppression. Different patients respond differently to the same therapy and overall survival of patients varies. Thus, there is a need to identify improved diagnostic and therapeutic methods.
A number of gene expression and tissue characterization methods have been developed to classify different lymphoma types based on their molecular signature. Such classifications may help predict the patients' responses to particular therapies. See US2011/0223157, US2007/0105136, US2009/0203050, and De and Brown, 2010, Int J Clin Exp Med 3: 55-68.